The objectives for this trial included assessment of overall survival, response rate and toxicity of this regimen.

Patients were eligible if they had: previously untreated SCC of the head and neck, with an identified primary site excluding lip, nasopharynx, sinus or salivary gland; stage III/IV disease; ECOG performance status of 0-1; adequate hematologic, renal and hepatic function;, and were able to provide informed consent.

Following induction therapy, patients with stable disease or a response to chemotherapy were given radiation therapy concurrent with cisplatin (100 mg/m2 IV q 21 days x 2).

Radiation was given using accelerated fractionation with a concomitant boost: 54 Gy in 1.8 Gy fractions with an additional concomitant 18 Gy added in 1.5 Gy fractions given over the last 12 treatment days.

Surgery was offered to patients after induction therapy if they had progressive but still resectable disease.

Surgery was offered to patients after concurrent chemoradiotherapy if they had residual or recurrent disease at the primary site or in the neck.

A neck dissection was considered in patients with N2 or greater disease at presentation.

76 patients were accrued and 2 of them were ineligible secondary to metastatic disease.

Oropharynx (47%) and larynx (32%) were the most common primary sites.

The median age of patients was 54 years.

Results

68 of the 74 eligible patients completed induction therapy and 50 patients (68%) finished concurrent chemoradiotherapy with toxicity as the most common cause cited to explain why patients did not receive the intended regimen.

59% of patients had grade 3 or 4 neutropenia after induction therapy and 85% of patients had at least one grade 3 or 4 toxicity following induction therapy.

Grade 3 or 4 mucositis was seen in 48% of patients during concurrent therapy.

Overall, 91% of patients experienced at least one grade 3 or 4 toxicity with this regimen.

After all therapy, a complete response rate at the primary site and neck was seen in 30% of patients.

Median follow-up is 31 months.

The 2 year projected progression free survival is 66% using a Kaplan Meier estimate (95% confidence interval from 55% to 77%)

The 2 year projected overall survival is 71% using a Kaplan Meier estimate (95% confidence interval from 61% to 81%).

Author's Conclusions

TPF induction chemotherapy followed by concurrent chemotherapy and accelerated fractionation with a concomitant boost is a toxic treatment regimen.

Although this toxicity strains the limits of acceptability for a cooperative group trial, the regimen proved feasible and could be completed in 68% of patients.

In this cohort of patients with advanced head and neck squamous carcinoma, the progression free and overall survivals were very encouraging.

Careful study of this kind of sequential treatment will be required before it can be adopted as a treatment standard.

Clinical/Scientific Implications

The authors presented a well designed phase II trial that combined a number of techniques that have all showed promising results on their own (induction chemotherapy, concurrent chemoradiotherapy with cisplatin, and accelerated fractionation). Before the first patient was treated on this trial, anyone with experience treating head and neck cancer knew that this was going to be a toxic regimen. With over 91% of patients experiencing grade >3 toxicity and only 68% of patients able to finish therapy, the feasibility of this regimen is certainly in question. The feasibilities seen in other cooperative groups using chemoradiotherapy range between 55% and 86%. However, these numbers improve to 83 to 86% if patients had single agent cisplatin concurrent with radiation (even using altered fractionation) without induction chemotherapy. Adding adjuvant, induction, or multi-agent chemotherapy to radiotherapy or chemoradiotherapy produced feasibilities in the 55 to 78% range, which are more in line with this trial. The concern is that these aggressive regimens may not improve outcomes if they can't be completed as often. This regimen may make sense in certain patients, but patients need to be carefully selected in terms of age, performance status and prognostic factors. Over 30% of these patients had N0 or N1 disease, and may not have needed induction therapy considering a lower risk of metastatic disease. With further follow-up and data maturation, we may be able to get a better understanding of which patients really may need such aggressive therapy. Until then, this regimen needs to remain firmly in the "experimental" category.